Application of (2, 6-dimethylphenyl) quinoxaline diamine derivative in preparation of antitumor drug composition

Abstract

The invention belongs to the technical field of antitumor drugs, and particularly discloses application of a (2, 6-dimethylphenyl) quinoxaline diamine derivative in preparation of an antitumor drug composition. The (2, 6-dimethylphenyl) quinoxaline diamine derivative provided by the invention has a remarkable inhibition effect on colon cancer, liver cancer, lung cancer, prostatic cancer, cervical cancer, glial cancer and breast cancer, shows excellent anti-tumor characteristics, can be used as an anti-tumor lead drug molecule, and has a good development and application prospect in the aspect of developing anti-tumor drugs.

Description

Technical Field

[0001] The present invention belongs to the technical field of anti-tumor drugs, and relates to the application of a quinoxaline diamine derivative in the preparation of an anti-tumor drug composition, and specifically relates to the application of a (2,6-dimethylphenyl)quinoxaline diamine derivative in the preparation of an anti-tumor drug composition. Background Art

[0002] Cancer, also known as malignant tumor, is indeed a disease that poses a major threat to human health and life span. It originates from the cells of the body, and when these cells proliferate abnormally and lose the functions and regulation of normal cells, tumors are formed. These tumor cells are able to invade surrounding tissues and may spread to other parts of the body through the blood or lymphatic system to form new tumors, namely metastases.

[0003] The impact of cancer on human health is multifaceted, including (1) Life threat: Cancer is one of the leading causes of death worldwide, especially in developed countries and certain areas of developing countries. Many types of cancer are difficult to detect in the early stages, and even after detection, treatment can be complicated and expensive, leading to a poor prognosis. (2) Decreased quality of life: Cancer patients often experience physical symptoms such as pain, fatigue, nausea, and vomiting, which can seriously affect their quality of life. In addition, cancer treatments such as chemotherapy, radiotherapy, and surgery can also bring a series of side effects, further exacerbating patients' discomfort. (3) Psychological stress: The diagnosis and treatment process of cancer is not only physically challenging, but also puts great psychological pressure on patients. Emotional problems such as fear, anxiety, and depression are common among cancer patients, and these psychological problems may further affect their treatment outcomes and quality of life. (4) Economic burden: The cost of cancer treatment is usually high, including examination fees, surgery fees, drug fees, rehabilitation fees, etc. For many families, these costs may be difficult to afford, resulting in an increased economic burden.

[0004] In order to cope with the threat of cancer to human health, countries around the world are increasing their investment in cancer research and prevention. This includes improving the early screening rate of cancer, developing new treatments, and strengthening public health education. At the same time, scientists are also constantly exploring the pathogenesis of cancer in order to find more effective prevention and treatment methods.

[0005] In conclusion, cancer, as a serious malignant tumor, has a significant impact on human health and life expectancy. We need to work together to meet this challenge through a variety of means such as scientific research, health education and social support.

[0006] Currently, quinoxaline derivatives are becoming a hot topic in anti-tumor drug research due to their diverse biological activities and potential pharmacological effects.

[0007] For example, the prior art discloses: 1. Chinese patent: CN202410512254 Application of aminoquinoxaline derivatives in the preparation of antitumor drug compositions. The present invention belongs to the field of antitumor drug technology, and specifically discloses the application of 2,3-diaminoquinoxaline derivatives in the preparation of antitumor drug compositions. The 2,3-diaminoquinoxaline derivatives provided by the present invention have significant inhibitory effects on colon cancer, liver cancer, lung cancer, prostate cancer, cervical cancer, glial cancer and breast cancer, and exhibit excellent antitumor properties. They can be used as antitumor lead drug molecules and have good development and application prospects in the development of antitumor drugs. 2. Chinese patent: CN202210164476.3 The present invention belongs to the field of organic chemical synthesis, and discloses a 4-aminoquinoline compound and its preparation method and application in antitumor drugs. It is a general formula (I) structure, wherein R is selected from hydrogen, alkyl, alkoxy, halogen, nitro; R1 is selected from hydrogen, alkyl, aryl. The invention allows the alkyne amide raw material to undergo self-cyclization under non-metal catalysis, and then removes the protecting group of the cyclization product to obtain a 4-aminoquinoline compound. The preparation method has the advantages of being environmentally friendly, readily available raw materials, simple reaction steps, high yield, and wide substrate universality. The 4-aminoquinoline compound has the activity of resisting human bladder cancer cells 5637, human glioblastoma cells A172, human malignant melanoma cells A375, human cervical cancer cells C33A, human colon cancer cells HCT 116 and SW480, human cervical cancer cells Hela, human pancreatic cancer cells CFPAC-1, human liver cancer cells Hep G2, human lung cancer cells A549 and human breast cancer cells MCF-7, and can be applied to drug development.

[0008] However, there are currently no reports on the anti-tumor biological activity or clinical application of (2,6-dimethylphenyl)quinoxaline diamine derivatives. Summary of the invention

[0009] The present invention provides a novel application of quinoxaline diamine derivatives in the preparation of anti-tumor drug compositions.

[0010] The first object of the present invention is to provide a (2,6-dimethylphenyl)quinoxaline diamine derivative having a chemical structural formula as shown below:

[0011]

[0012] Among them, R1 is one of a hydrogen group, a pentyl group, a trifluoropentyl group and a bromo group; R2 is one of a hydrogen group, a bromo group and a methyl group; and R3 is one of a hydrogen group and a methyl group.

[0013] It is further specified that the tumors include but are not limited to colon cancer, liver cancer, lung cancer, prostate cancer, cervical cancer, glial cancer and breast cancer.

[0014] Further explanation, R1 is hydrogen (H), pentyl Trifluoropentyl and bromo (Br); R2 is hydrogen (H), bromo (Br) and methyl One of: R3 is a hydrogen group (H) and a methyl group One of them.

[0015] Further explanation, the above (2,6-dimethylphenyl)quinoxaline diamine derivative is catalytically synthesized by the following steps, specifically:

[0016]

[0017] Take a 25ml reaction tube, add o-phenylenediamine derivative 1 (0.1mmol), 2,6-dimethylphenyl isocyanide 2 (0.25mmol), Pd(OAc)2 (5mol%), lithium bromide (1.0equiv), silver nitrate (2.0equiv), cesium carbonate (3.0equiv) and dimethyl sulfoxide (1mL) into the reaction tube in sequence, and continue to react at 100℃ for 1 hour. After the reaction is completed, add 10mL of water to quench the reaction, extract with ethyl acetate three times (3×10mL), recover the organic layer, and concentrate it with a rotary evaporator. The crude product is separated by column chromatography to obtain the target product 3, and the developing solvent used is petroleum ether / ethyl acetate (10 / 1). The product is then confirmed by nuclear magnetic resonance and high-resolution mass spectrometry characterization methods.

[0018] The second object of the present invention is to provide the use of (2,6-dimethylphenyl)quinoxaline diamine derivatives in the preparation of anti-tumor pharmaceutical compositions.

[0019] It is further explained that the use of the (2,6-dimethylphenyl)quinoxaline diamine derivatives in the preparation of anti-tumor drug compositions is to use the (2,6-dimethylphenyl)quinoxaline diamine derivatives as candidate drugs or lead compounds for treating tumors, and to utilize the (2,6-dimethylphenyl)quinoxaline diamine derivatives to have inhibitory activity against a variety of tumor cells, thereby laying the foundation for the development of new anti-tumor drugs.

[0020] It is further described that the (2,6-dimethylphenyl)quinoxaline diamine derivative is used in the preparation of an anti-tumor pharmaceutical composition, and the therapeutic object of the pharmaceutical composition is a mammal or a human.

[0021] Further description, the use of the (2,6-dimethylphenyl)quinoxaline diamine derivative in the preparation of an anti-tumor pharmaceutical composition, wherein the pharmaceutical composition is prepared into a clinically acceptable pharmaceutical preparation using the (2,6-dimethylphenyl)quinoxaline diamine derivative as a main component and pharmaceutically acceptable excipients or auxiliary components;

[0022] It is further explained that the content of the (2,6-dimethylphenyl)quinoxaline diamine derivative in the pharmaceutical composition is usually 0.1-95.0% (w / w).

[0023] It is further described that the (2,6-dimethylphenyl)quinoxaline diamine derivative is used in the preparation of an anti-tumor pharmaceutical composition, and the pharmaceutical preparation includes two dosage forms: an oral preparation and an injection preparation.

[0024] It is further described that the use of the (2,6-dimethylphenyl)quinoxaline diamine derivative in the preparation of an anti-tumor pharmaceutical composition, the oral preparation is an oral capsule, and the injection preparation is an intravenous injection.

[0025] Generally speaking, as a drug, it is clinically used after being prepared into a preparation. The pharmaceutical composition of the present invention can be prepared according to methods known in the art as a pharmaceutical composition. The pharmaceutical composition of the present invention can be combined with one or more pharmaceutically acceptable solid or liquid excipients and / or adjuvants to prepare any dosage form suitable for human or animal use.

[0026] The pharmaceutical composition of the present invention or a pharmaceutical composition containing the same can be administered in a unit dosage form, and the administration route can be enteral or parenteral, such as oral, intravenous, intramuscular, subcutaneous, nasal, oral mucosa, eyes, lungs and respiratory tract, skin, vagina, rectum, etc.

[0027] The dosage form can be a liquid dosage form, a solid dosage form or a semisolid dosage form. Liquid dosage forms can be solutions (including true solutions and colloidal solutions), emulsions (including o / w types, w / o types and multiple emulsions), suspensions, injections (including water injections, powder injections and infusions), eye drops, nasal drops, lotions and liniments, etc.; solid dosage forms can be tablets (including ordinary tablets, enteric-coated tablets, lozenges, dispersible tablets, chewable tablets, effervescent tablets, orally disintegrating tablets), capsules (including hard capsules, soft capsules, enteric-coated capsules), granules, powders, micropills, dropping pills, suppositories, films, patches, aerosols (powders), sprays, etc.; semisolid dosage forms can be ointments, gels, pastes, etc.

[0028] The pharmaceutical composition of the present invention can be made into a common preparation, or a sustained-release preparation, a controlled-release preparation, a targeted preparation, and various microparticle delivery systems. In order to make the pharmaceutical composition of the present invention into tablets, various excipients known in the art can be widely used, including diluents, binders, wetting agents, disintegrants, lubricants, and glidants. The diluent may be starch, dextrin, sucrose, glucose, lactose, mannitol, sorbitol, xylitol, microcrystalline cellulose, calcium sulfate, calcium hydrogen phosphate, calcium carbonate, etc.; the wetting agent may be water, ethanol, isopropanol, etc.; the adhesive may be starch slurry, dextrin, syrup, honey, glucose solution, microcrystalline cellulose, acacia slurry, gelatin slurry, sodium carboxymethyl cellulose, methyl cellulose, hydroxypropyl methyl cellulose, ethyl cellulose, acrylic resin, carbomer, polyvinyl pyrrolidone, polyethylene glycol, etc.; the disintegrant may be dry starch, microcrystalline cellulose, low-substituted hydroxypropyl cellulose, cross-linked polyvinyl pyrrolidone, cross-linked sodium carboxymethyl cellulose, sodium carboxymethyl starch, sodium bicarbonate and citric acid, polyoxyethylene sorbitan fatty acid ester, sodium dodecyl sulfate, etc.; the lubricant and glidant may be talc, silicon dioxide, stearate, tartaric acid, liquid paraffin, polyethylene glycol, etc.

[0029] The tablets can be further made into coated tablets, such as sugar-coated tablets, film-coated tablets, enteric-coated tablets, or double-layer tablets and multi-layer tablets.

[0030] In order to prepare the dosing unit into a capsule, the active ingredient pharmaceutical composition of the present invention can be mixed with a diluent and a glidant, and the mixture can be directly placed in a hard capsule or a soft capsule. The active ingredient pharmaceutical composition of the present invention can also be first prepared into granules or pellets with a diluent, a binder, and a disintegrant, and then placed in a hard capsule or a soft capsule. The diluents, binders, wetting agents, disintegrants, and glidants used to prepare the tablets of the pharmaceutical composition of the present invention can also be used to prepare the capsules of the pharmaceutical composition of the present invention.

[0031] To prepare the pharmaceutical composition of the present invention into an injection, water, ethanol, isopropanol, propylene glycol or a mixture thereof can be used as a solvent and an appropriate amount of a solubilizer, a cosolvent, a pH adjuster, and an osmotic pressure regulator commonly used in the art can be added. The solubilizer or cosolvent can be poloxamer, lecithin, hydroxypropyl-β-cyclodextrin, etc.; the pH adjuster can be phosphate, acetate, hydrochloric acid, sodium hydroxide, etc.; the osmotic pressure regulator can be sodium chloride, mannitol, glucose, phosphate, acetate, etc. If a lyophilized powder injection is prepared, mannitol, glucose, etc. can also be added as a support agent.

[0032] Furthermore, if necessary, colorants, preservatives, perfumes, flavoring agents or other additives may be added to the pharmaceutical preparations.

[0033] Compared with the prior art, the present invention has the following advantages:

[0034] 1. The application of the quinoxaline diamine derivatives developed by the present invention in the preparation of anti-tumor drug compositions has significant medical value and broad application prospects. In particular, the application of (2,6-dimethylphenyl)quinoxaline diamine derivatives in anti-tumor is particularly prominent. The R1, R2 and R3 groups in its chemical structure give the derivatives unique biological activity, making them have significant inhibitory effects on a variety of tumors. The (2,6-dimethylphenyl)quinoxaline diamine derivatives are synthesized from o-phenylenediamine derivatives and 2,6-dimethylphenyl isonitrile, using Pd(OAc)2 (5mol%) as a catalyst, combined with lithium bromide (1.0equiv), silver nitrate (2.0equiv) and cesium carbonate (3.0equiv) and other cheap and readily available raw materials, to achieve efficient synthesis of (2,6-dimethylphenyl)quinoxaline diamine derivatives under mild conditions. This synthesis method not only simplifies the preparation process and reduces production costs, but also helps to achieve industrial production, laying a foundation for the large-scale application of drugs. The successful development and application of (2,6-dimethylphenyl)quinoxaline diamine derivatives are expected to bring more effective treatments to cancer patients, improve their quality of life, and reduce the social medical burden. At the same time, the synthesis method of the derivatives is simple and low-cost, which helps to reduce drug prices and benefit more patients.

[0035] 2. The present invention verifies the application of (2,6-dimethylphenyl)quinoxaline diamine derivatives in the preparation of anti-tumor drug compositions through experiments. The anti-tumor range is wide, and (2,6-dimethylphenyl)quinoxaline diamine derivatives show good inhibitory activity against colon cancer, liver cancer, lung cancer, prostate cancer, cervical cancer, glial cancer and breast cancer. The research results show that the inhibitory effect of (2,6-dimethylphenyl)quinoxaline diamine derivatives on tumor cells is better than that of the positive drug 5-fluorouracil. BRIEF DESCRIPTION OF THE DRAWINGS

[0036] Figure 1 The figure is a chemical structural formula diagram of the (2,6-dimethylphenyl)quinoxaline diamine derivative of the present invention. DETAILED DESCRIPTION

[0037] The specific implementation modes of the present invention are further described below in conjunction with examples.

[0038] Embodiment 1:

[0039] The (2,6-dimethylphenyl)quinoxaline diamine derivative is prepared by the following synthetic route, and the specific steps are as follows:

[0040]

[0041] Take a 25ml reaction tube, add o-phenylenediamine derivative 1 (0.1mmol), 2,6-dimethylphenyl isocyanide 2 (0.25mmol), Pd(OAc)2 (5mol%), lithium bromide (1.0equiv), silver nitrate (2.0equiv), cesium carbonate (3.0equiv) and dimethyl sulfoxide (1mL) into the reaction tube in sequence, and continue to react at 100℃ for 1 hour. After the reaction is completed, add 10mL of water to quench the reaction, extract with ethyl acetate three times (3×10mL), recover the organic layer, and concentrate it with a rotary evaporator. The crude product is separated by column chromatography to obtain the target product 3, and the developing solvent used is petroleum ether / ethyl acetate (10 / 1). The product is then confirmed by nuclear magnetic resonance and high-resolution mass spectrometry characterization methods.

[0042] Embodiment 2:

[0043] Compound 1 is prepared by the following synthetic route, and the specific steps are as follows: take a 25 ml reaction tube, add o-phenylenediamine (0.1 mmol), 2,6-dimethylphenyl isocyanide (0.25 mmol), Pd(OAc)2 (5 mol%), lithium bromide (1.0 equiv), silver nitrate (2.0 equiv), cesium carbonate (3.0 equiv) and dimethyl sulfoxide (1 mL) into the reaction tube in sequence, and continue the reaction at 100° C. for 1 hour to obtain the target compound (compound 1, whose structural formula is shown in the figure below), and the yield is 89%.

[0044] The technical route for preparing compound 1 is as follows:

[0045]

[0046] The characterization data of compound 1 are as follows: 1 H NMR (500MHz, DMSO, δppm) 8.34 (s, 2H), 7.29-7.27 (m, 2H), 7.20-7.13 (m, 8H), 2.24 (s, 12H); 13 C NMR(126MHz,DMSO,δppm)142.5,137.2,137.0,135.9,128.5,126.8,125.5,124.6,18.8.HRMS(ESI)m / z:calcd for C 24 H 25 N4[M+H] + 369.2079; found 369.2083.

[0047] Embodiment 3:

[0048] Compound 2 is prepared by the following synthetic route, and the specific steps are as follows: take a 25 ml reaction tube, add 4-tert-butyl o-phenylenediamine (0.1 mmol), 2,6-dimethylphenyl isocyanide (0.25 mmol), Pd(OAc)2 (5 mol%), lithium bromide (1.0 equiv), silver nitrate (2.0 equiv), cesium carbonate (3.0 equiv) and dimethyl sulfoxide (1 mL) into the reaction tube in sequence, and continue the reaction at 100° C. for 1 hour to obtain the target compound (compound 2, whose structural formula is shown in the figure below), and the yield is 55%.

[0049] The technical route for preparing compound 2 is as follows:

[0050]

[0051] The characterization data of compound 2 are as follows: 1 H NMR (400MHz, DMSO, δppm)8.25(s,1H),8.21(s,1H),7.25-7.09(m,11H),2.22(s,6H),2.21(s,6H),1.25(s,9H); 13 C NMR (101MHz, DMSO, δppm)147.2,142.6,142.3,137.1,137.1,136.8,136.0,135.9,135.1, 128.6,128.5,126.8,126.7,125.0,122.6,121.2,34.7,31.8,18.8.HRMS(ESI)m / z:calcd for C 28 H 33 N4[M+H] + 425.2708; found 425.2705.

[0052] Embodiment 4:

[0053] Compound 3 was prepared by the following synthetic route, and the specific steps are as follows: take a 25 ml reaction tube, add 4-trifluoromethyl o-phenylenediamine (0.1 mmol), 2,6-dimethylphenyl isocyanide (0.25 mmol), Pd(OAc)2 (5 mol%), lithium bromide (1.0 equiv), silver nitrate (2.0 equiv), cesium carbonate (3.0 equiv) and dimethyl sulfoxide (1 mL) into the reaction tube in sequence, and continue the reaction at 100 ° C for 1 hour to obtain the target compound (compound 3, whose structural formula is shown in the figure below), and the yield is 85%.

[0054] The technical route for preparing compound 3 is as follows:

[0055]

[0056] The characterization data of compound 3 are as follows: 1 H NMR (400MHz, DMSO, δppm)8.70(s,1H),8.61(s,1H),7.52(s,1H),7.44-7.36(m,2H),7.20-7.07(m,6H),2.22(s,12H); 13 C NMR (101MHz, DMSO, δppm)143.9,143.4,139.6,136.6,136.4,136.3,135.9,135.9,128.6,128.2,127.2,1 27.1, 126.4, 124.6 (q, J = 272.9Hz), 124.2 (q, J = 31.8Hz), 121.91 (q, J = 3.7Hz), 120.2 (d, J = 3.6Hz), 18.2. 19 FNMR(376MHz,DMSO,δppm)-62.10.HRMS(ESI)m / z:calcd for C 25 H 24 N4F3[M+H] + 437.1953; found 437.1957.

[0057] Embodiment 5:

[0058] Compound 4 was prepared by the following synthetic route, and the specific steps are as follows: take a 25 ml reaction tube, add 4-bromo-o-phenylenediamine (0.1 mmol), 2,6-dimethylphenyl isocyanide (0.25 mmol), Pd(OAc)2 (5 mol%), lithium bromide (1.0 equiv), silver nitrate (2.0 equiv), cesium carbonate (3.0 equiv) and dimethyl sulfoxide (1 mL) into the reaction tube in sequence, and continue the reaction at 100° C. for 1 hour to obtain the target compound (compound 4, whose structural formula is shown in the figure below), and the yield is 90%.

[0059] The technical route for preparing compound 4 is as follows:

[0060]

[0061] The characterization data of compound 4 are as follows: 1 H NMR (400MHz, DMSO, δppm) 8.54 (s, 1H), 8.48 (s, 1H), 7.41 (s, 1H), 7.41 (s, 1H), 7.23 (d, J = 2.1Hz, 1H), 7.18-7.15 (m, 6H), 2.22 (s, 12H);13 C NMR (101MHz, DMSO, δppm)143.1142.8,138.5,136.7,136.6,136.3,135.9,135. 8,128.6,127.3,127.2,127.0,126.9,116.5,18.8,18.7.HRMS(ESI)m / z:calcd for C 24 H 24 N4B r [M+H] + 447.1184; found 447.1186.

[0062] Embodiment 6:

[0063] Compound 5 was prepared by the following synthetic route, and the specific steps are as follows: take a 25 ml reaction tube, add 4,5-dibromo-o-phenylenediamine (0.1 mmol), 2,6-dimethylphenyl isocyanide (0.25 mmol), Pd(OAc)2 (5 mol%), lithium bromide (1.0 equiv), silver nitrate (2.0 equiv), cesium carbonate (3.0 equiv) and dimethyl sulfoxide (1 mL) into the reaction tube in sequence, and continue the reaction at 100° C. for 1 hour to obtain the target compound (compound 5, whose structural formula is shown in the figure below), with a yield of 82%.

[0064] The technical route for preparing compound 5 is as follows:

[0065]

[0066] The characterization data of compound 5 are as follows: 1 H NMR (500MHz, DMSO, δppm)8.64(s,2H),7.57(s,2H),7.19(s,6H),2.21(s,12H); 13 C NMR(126MHz,DMSO,δppm)143.3,137.5,136.3,135.9,129.1,128.6127.2,118.2,18.7.HRMS(ESI)m / z:calcd for C 24 H 23 N4Br[M+H] + 525.0289; found 525.0291.

[0067] Embodiment 7:

[0068] Compound 6 was prepared by the following synthetic route, and the specific steps are as follows: take a 25 ml reaction tube, add 4-methyl-5-bromo-o-phenylenediamine (0.1 mmol), 2,6-dimethylphenyl isocyanide (0.25 mmol), Pd(OAc)2 (5 mol%), lithium bromide (1.0 equiv), silver nitrate (2.0 equiv), cesium carbonate (3.0 equiv) and dimethyl sulfoxide (1 mL) into the reaction tube in sequence, and continue the reaction at 100° C. for 1 hour to obtain the target compound (compound 6, whose structural formula is shown in the figure below), and the yield is 80%.

[0069] The technical route for preparing compound 6 is as follows:

[0070]

[0071] The characterization data of compound 6 are as follows: 1 H NMR (500MHz, DMSO, δppm)8.44(s,1H),8.42(s,1H),7.44(s,1H),7.27(s,1H),7.18-7.16(m,6H),2.30(s,3H),2.21(s,12H); 13 CNMR(126MHz,DMSO,δppm)144.1,143.1,142.9,136.9,136.8,136.6,136.5,136.0,13 5.9,132.8,128.5,127.6,126.8,126.7,119.5,22.6,18.8,18.7.HRMS(ESI)m / z:calcd for C 25 H 26 N4Br[M+H] + 461.1341; found 461.1345.

[0072] Embodiment 8:

[0073] Compound 7 was prepared by the following synthetic route, and the specific steps are as follows: take a 25 ml reaction tube, add 3-methyl-5-bromo-o-phenylenediamine (0.1 mmol), 2,6-dimethylphenyl isocyanide (0.25 mmol), Pd(OAc)2 (5 mol%), lithium bromide (1.0 equiv), silver nitrate (2.0 equiv), cesium carbonate (3.0 equiv) and dimethyl sulfoxide (1 mL) into the reaction tube in sequence, and continue the reaction at 100° C. for 1 hour to obtain the target compound (compound 7, whose structural formula is shown in the figure below) with a yield of 44%.

[0074] The technical route for preparing compound 7 is as follows:

[0075]

[0076] The characterization data of compound 7 are as follows: 1 H NMR (400MHz, DMSO, δppm)8.51(s,1H),8.42(s,1H),7.24(s,1H),7.23(s,1H),7.20-7.16(m,6H),2.24(s,6H),2.21(s,6H),2.16(s,3H); 13 C NMR (101MHz, DMSO, δppm)142.8,141.5,138.1,136.7,136.6,135.9,135.5,134.6,128 .5,128.3,127.4,126.9,126.6,125.1,116.1,18.9,18.7,16.5.HRMS(ESI)m / z:calcd forC 25 H 26 N4Br[M+H] + 461.1341; found 461.1346.

[0077] The beneficial effects of the drug of the present invention are further described below through pharmacodynamic tests and comparative tests. The tumor cell lines used in the experiments of the present invention are drugs for preparing tumors formed by human colon cancer cells HCT116, human liver cancer cells HepG-2, human lung cancer cells A549, human prostate cancer cells PC3, human cervical cancer cells Hela, human glial cancer cells U87, and human malignant breast cancer cells 4T1.

[0078] In vitro anti-tumor cell activity test of (2,6-dimethylphenyl)quinoxaline diamine derivatives:

[0079] 1. Cells and drugs:

[0080] Human colon cancer cells HCT116, human liver cancer cells HepG-2, human lung cancer cells A549, human prostate cancer cells PC3, human cervical cancer cells Hela, human glial cancer cells U87, and human malignant breast cancer cells 4T1 were purchased from the Shanghai Cell Bank of the Chinese Academy of Sciences;

[0081] Positive drug: 5-fluorouracil (5-Fu), purchased from Sigma Aldrich Company (St. Louis, MO, USA), purity >99.5% (HPLC).

[0082] 2. Experimental Methods

[0083] Take 5.0×10 tumor cells in the logarithmic growth phase 4cells / mL were inoculated into 96-well plates, 200 μL per well, and cultured at 37°C and 5% CO2 for 24 h;

[0084] Dissolve the test sample with dimethyl sulfoxide (DMSO), and then use fresh culture medium to prepare a sample culture solution with a final concentration of 1.0-100 μM, add it to a 96-well plate, and incubate it at 37°C and 5% CO2 for 24 hours;

[0085] Remove the culture medium, add 100 μL of 0.5 mg / mL MTT to each well, and incubate at 37°C and 5% CO2 for 3-4 h; carefully remove the culture medium, add 100 μL DMSO, and shake thoroughly to dissolve the crystals;

[0086] The microplate reader uses 570nm as the experimental wavelength and 630nm as the reference wavelength to detect the absorbance value. 50 The values ​​were calculated using the LOGIT method.

[0087] 3. Experimental results

[0088] As shown in Table 1, the experimental results show that (2,6-dimethylphenyl)quinoxaline diamine derivatives have obvious inhibitory effects on human colon cancer cells HCT116, human liver cancer cells HepG-2, human lung cancer cells A549, human prostate cancer cells PC3, human cervical cancer cells Hela, human glial cancer cells U87, and human malignant breast cancer cells 4T1. 50 The values ​​are between 0.62-61.54μmol / L.

[0089] Table 1 IC values ​​of (2,6-dimethylphenyl)quinoxaline diamine derivatives on various tumor cells 50 value

[0090]

[0091]

[0092] In summary, the (2,6-dimethylphenyl) quinoxaline diamine derivatives of the present invention have a significant inhibitory effect on colon cancer, liver cancer, lung cancer, prostate cancer, cervical cancer, glioma and breast cancer, and show excellent anti-tumor properties. The derivatives, as anti-tumor lead drug molecules, have very important research and development value. Through in-depth research on its mechanism of action, we can further understand its mechanism of action in anti-tumor, thereby providing a more solid theoretical basis for its application in drug research and development. Therefore, the (2,6-dimethylphenyl) quinoxaline diamine derivatives of the present invention have huge development and application prospects in the field of anti-tumor drug research and development. Through further research and optimization, we are expected to develop more efficient and safe anti-tumor drugs, provide new treatment options for cancer patients, and make greater contributions to human health.

[0093] Although the present invention has been described in detail above with general descriptions and specific embodiments, it is obvious to those skilled in the art that some modifications or improvements may be made thereto based on the present invention. Therefore, these modifications or improvements made without departing from the spirit of the present invention all fall within the scope of protection claimed by the present invention.

Claims

1. Use of a quinoxaline diamine derivative in the preparation of an anti-tumor pharmaceutical composition, characterized in that: Specifically, it is the use of (2,6-dimethylphenyl)quinoxaline diamine derivatives in the preparation of anti-tumor drug compositions; The chemical structural formula of the (2,6-dimethylphenyl)quinoxaline diamine derivative is as follows: Among them, R1 is one of a hydrogen group, a pentyl group, a trifluoropentyl group and a bromo group; R2 is one of a hydrogen group, a bromo group and a methyl group; and R3 is one of a hydrogen group and a methyl group.

2. The use of a quinoxaline diamine derivative according to claim 1 in the preparation of an anti-tumor pharmaceutical composition, characterized in that: The tumors include, but are not limited to, colon cancer, liver cancer, lung cancer, prostate cancer, cervical cancer, glioma and breast cancer.

3. The use of a quinoxaline diamine derivative according to claim 1 in the preparation of an anti-tumor pharmaceutical composition, characterized in that: The invention relates to using (2,6-dimethylphenyl)quinoxaline diamine derivatives as candidate drugs or lead compounds for treating tumors.

4. The use of a quinoxaline diamine derivative according to claim 1 in the preparation of an anti-tumor pharmaceutical composition, characterized in that: The therapeutic object of the pharmaceutical composition is a mammal or a human.

5. Use of a quinoxaline diamine derivative according to claim 1 in the preparation of an anti-tumor pharmaceutical composition, characterized in that: The pharmaceutical composition is prepared into a clinically accepted pharmaceutical preparation by using a (2,6-dimethylphenyl)quinoxaline diamine derivative as a main component and adding auxiliary materials or auxiliary components accepted in pharmacy.

6. Use of a quinoxaline diamine derivative according to claim 5 in the preparation of an anti-tumor pharmaceutical composition, characterized in that: The content of the (2,6-dimethylphenyl)quinoxaline diamine derivative in the pharmaceutical composition is usually 0.1-95.0% w / w.

7. Use of a quinoxaline diamine derivative according to claim 5 in the preparation of an anti-tumor pharmaceutical composition, characterized in that: The pharmaceutical preparations include two dosage forms: oral preparations and injection preparations.

8. Use of a quinoxaline diamine derivative according to claim 7 in the preparation of an anti-tumor pharmaceutical composition, characterized in that: The oral preparation is an oral capsule, and the injection preparation is an intravenous injection solution.

Images